Abstract

Background

We conducted a phase Ib dose-confirmation study of indoximod with radiation, followed by indoximod with cyclic temozolomide therapy, to evaluate safety and overall survival (OS) in children with newly diagnosed DIPG (diffuse intrinsic pontine glioma). Indoximod is a small-molecule inhibitor of the IDO pathway that reverses immune suppression imposed by tumor microenvironments. DIPG is a uniformly fatal orphan disease with no curative treatment options.

Methods

Children age 3 to 21 years, with newly diagnosed DIPG were eligible for treatment with oral indoximod (38.4 mg/kg/day divided BID, throughout) combined with fractionated conformal radiation therapy (54 Gy in 30 fractions), followed by cyclic oral chemo-immunotherapy using indoximod combined with temozolomide (200 mg/m2/day, days 1-5 of each 28-day cycle). The indoximod dose was the previously determined recommended phase-II dose (RP2D), and the study design called for phase I monitoring to confirm safety of this dose in DIPG patients.

Results

Thirteen children (median age 9 years, range 5 to 20 years) with newly diagnosed DIPG were treated using this indoximod-based radio-chemo-immunotherapy regimen. The 12-month OS was 62% (8/13) and estimated median OS was 14.5 months (follow-up range 4.8 to 22 months) with 4 patients remaining in follow-up. This compares favorably to the expected 12-month OS of approximately 45% and median OS of approximately 10.8 months from published historical controls (Kilburn, et al; 2017). Two patients experienced near-complete responses until showing relapse at 7.6 months and 13.3 months of study therapy. Patients were followed with quantitative volumetric analyses of MRIs and serial measurements of peripheral blood inflammatory monocytes, T cell activation, and pro-inflammatory cytokines. The most common adverse events attributed to indoximod were thrombocytopenia, diarrhea, nausea, vomiting, and fatigue.

Conclusion

Adding indoximod-based immunotherapy to conventional radiation and chemotherapy for up-front therapy of children with DIPG appears to be well tolerated with improved outcomes.

Clinical trial identification

NLG2105, NCT02502708.

Legal entity responsible for the study

NewLink Genetics Corporation.

Funding

NewLink Genetics Corporation, Alex's Lemonade Stand Foundation, Cannonball Kids cancer Foundation, Beloco Foundation, Eli’s Block Party Foundation, Hyundai Hope on Wheels Foundation, Northern Nevada Children’s Cancer Research Foundation, CAM Fund, Press On Foundation.

Disclosure

T.S. Johnson: Research grant / Funding (institution): NewLink Genetics Corporation. E.P. Kennedy: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. N. Vahanian: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. D.H. Munn: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: NewLink Genetics Corporation. All other authors have declared no conflicts of interest.

中文翻译：

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101P使用IDO途径抑制剂indoximod结合放疗和化疗的NLG2105 I期试验结果，用于新诊断为DIPG的儿童

抽象的

背景

我们进行了吲哚西莫放疗，然后进行环替莫唑胺治疗的吲哚西莫的Ib期剂量确证研究，以评估新诊断为DIPG（弥漫性桥脑神经胶质瘤）的儿童的安全性和总生存期（OS）。吲哚莫德是IDO途径的小分子抑制剂，可逆转由肿瘤微环境施加的免疫抑制作用。DIPG是一种致命的孤儿疾病，没有任何治疗选择。

方法

年龄在3到21岁之间，新诊断为DIPG的儿童符合以下条件：口服吲哚莫德（38.4 mg / kg /天，BID，全程），结合分形保形放射疗法（54 Gy，分30份），然后进行循环口服化学治疗。使用吲哚莫德联合替莫唑胺的免疫疗法（200 mg / m2 /天，每个28天周期的第1-5天）。吲哚莫德剂量是先前确定的推荐II期剂量（RP2D），该研究设计要求进行I期监测，以确认该剂量在DIPG患者中的安全性。

结果

使用这种基于吲哚莫德的放射化学免疫疗法方案治疗了13例新诊断为DIPG的儿童（中位年龄9岁，范围5至20岁）。12个月OS为62％（8/13），估计中位OS为14.5个月（随访范围4.8至22个月），其余4例仍在随访中。这与已公布的历史对照的预期12个月OS和中位OS分别约为45％和约10.8个月形成了鲜明对比（Kilburn等人; 2017）。两名患者经历了近乎完全的反应，直到在研究治疗的7.6个月和13.3个月出现复发为止。对患者进行MRI的定量体积分析，并对外周血炎症单核细胞，T细胞活化和促炎细胞因子进行系列测量。

结论

在常规放疗和化学疗法中添加基于吲哚昔莫的免疫疗法以对DIPG儿童进行前期治疗似乎具有良好的耐受性，并改善了预后。

临床试验鉴定

NLG2105，NCT02502708。

负责研究的法人实体

NewLink Genetics Corporation。

资金

NewLink Genetics Corporation，Alex的Lemonade Stand基金会，Cannonball Kids癌症基金会，Beloco基金会，Eli的Block Party基金会，现代希望车轮基金会，内华达州北部儿童癌症研究基金会，CAM基金，Press On基金会。

揭露

TS Johnson：研究资助/资助（机构）：NewLink Genetics Corporation。EP肯尼迪（EP Kennedy）：股东/股东/股票期权，全职/兼职，官员/董事会：NewLink Genetics Corporation。N. Vahanian：股东/股东/股票期权，全职/兼职，官员/董事会：NewLink Genetics Corporation。DH Munn：咨询/顾问，股东/股东/股票期权，许可/特许权使用费：NewLink Genetics Corporation。所有其他作者都声明没有利益冲突。